This program's objective is the delineation of the structural and functional relations between the isozymes of urease, and of the pharmacology of its hydroxamate inhibitors in relation to human disease and animal nutrition. Urease is perhaps the most suitable of all proteins for correlative structure- function studies of association- dissociation phenomena, because of its catalytics potency, its wide variety of non-genetic isozymes, and their slow equilibria, which make feasible the discrete analysis of individually isolated forms. Aggregate-state studies will depend primarily on ultracentrifugation and gel electrophoresis, while conformation and denaturation will be assessed by UV spectrophotometry, circular dichroism, and chemical reactivity. Isolated isozymes will be compared by catalytic assay for differences in specific activity, pH-activity curves, substrate activity ratios, inhibition patterns, and inactivation rates; and labelled complexes will be sought. The functional division of thiol groups in the enzyme will be investigated by chemical modification; and comparative study of a purified bacterial urease should give some insight into the evolutionary development of the molecule. The urease polymers will also provide a useful tool for analyzing the theory of gel eletrophoresis. The aliphatic hydroxamates are potentially useful agents in the treatment of hepatic coma, uremia, and sepsis or urinary-tract infectioLs with ureolytic bacteria; and for improving nitrogen retention in livestock maintained on non-protein-nitrogen diets. For these reasons the antagonism of ureolysis by these compounds must be documented in vitro, by enzymatic assay, and in vivo, using C14-urea. Their toxicology and disposition in animals must also be evaluated. This program should result in a better understanding of association & dissociation of proteins, and the role such phenomena may play in altering function, and may help to introduce a new group of drugs into clinical medicine and/or animal nutrition.